Benzopyrans as selective estrogen receptor β agonists (SERBAs). Part 4: Functionalization of the benzopyran A-ring

Structure activity relationship studies of the A-ring on the benzopyran scaffold. Benzopyrans are selective estrogen receptor (ER) β agonists (SERBAs), which bind the ER receptor subtypes α and β in opposite orientations. We have used structure based drug design to show that this unique phenomena can be exploited via substitution at the 8-position of the benzopyran A-ring to disrupt binding to ERα, thus improving ERβ subtype selectivity. X-ray cocrystal structures with ERα and ERβ are supportive of this approach to improve selectivity in this structural class.